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Journal of the National Cancer Institute Monographs, No. 27, 67-73, 2000
© 2000 Oxford University Press
Chapter 3: Endogenous Estrogens as Carcinogens Through
Metabolic Activation
James D. Yager
Correspondence to: James D. Yager, Ph.D., Division of Toxicological Sciences, Department of
Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, 615
North Wolfe St., Baltimore, MD 21205 (e-mail: [email protected]).
A common thread linking the main risks for developing breast cancer in women is
cumulative, excessive exposure to estrogen. The standard paradigm to account for this
association focuses on increased cell proliferation caused by estrogen through estrogen
receptor-mediated signal transduction accompanied by increased probability for
mutation to occur during DNA synthesis. This chapter provides an overview of the
mounting evidence, provided from cell culture and whole animal experimental studies, in
support of a role for the oxidative metabolites of estrogen, in particular, the catechol
estrogens, in the development of estrogen carcinogenesis. This provides a paradigm for
how estrogens may contribute to the development of human breast cancer. The
chapters that follow will fill in the details. Evidence shows that the catechols themselves
are signaling molecules that work through the estrogen receptor. In addition, upon
further oxidation, the catechols can give rise to reactive quinones capable of forming
direct adducts with glutathione and purines in DNA and of redox cycling to generate
reactive oxygen species that can cause oxidative damage. Estradiol and estrone, as
well as their 4-hydroxy catechols, are carcinogenic in the Syrian golden hamster kidney,
and ethinyl estradiol is a strong promoter of hepatocarcinogenesis in the rat. Increased
oxidative DNA damage has been detected in target tissues after estrogen treatment in
both animal model systems. Furthermore, several recent molecular epidemiologic
studies have found that a polymorphism associated with a low-activity form of catecholO-methyltransferase, an enzyme involved in the inactivation of catechol estrogens, is
associated with an increased risk for developing breast cancer. The increased risk is
observed in certain women, although the studies are not consistent on which subgroup
of women (e.g., premenopausal or postmenopausal) is at increased risk, and one study
detected no increased risk. Reasons for such discrepancies are discussed in light of
factors, such as genetic polymorphisms and environmental/lifestyle susceptibility factors,
which control the tissue-specific balance within cells among the estrogen metabolites. It
is concluded that such factors will have to be identified through additional mechanistic
studies and that, as they are identified, they can be incorporated into future molecular
epidemiologic studies designed to determine their actual impact on cancer risk in human